Doctors at the University of Alabama at Birmingham (UAB) are
enrolling patients in an international clinical trial to find out if
inhaled nitric oxide benefits those with novel coronavirus (COVID-19)
who have severely damaged lungs.
Right now, there are no approved treatments for the illness caused by COVID-19. The severe form of lung failure—acute respiratory distress syndrome—is the leading cause of death in COVID-19. Nitric oxide has been found to improve blood flow in areas of the lungs still receiving air, increasing the amount of oxygen in the blood stream.
Along with being used to treat failing lungs, nitric oxide
has been found to have antiviral properties against coronaviruses. That
was shown during the 2002 to 2003 severe acute respiratory syndrome
outbreak, which was caused by a coronavirus similar to the one that
causes COVID-19. Any COVID-19 patient in UAB’s intensive care unit who
is using a ventilator to breathe may qualify for the study.
“This trial will allow the sickest COVID-19 patients at UAB access to
a rescue therapy that may have antiviral benefits in addition to
improving the status of lungs,” Vibhu Parcha, M.D., research fellow in
the UAB Division of Cardiovascular Disease, said in a university news
release.
https://medicalxpress.com/news/2020-04-clinical-trial-underway-nitric-oxide.html
Saturday, April 11, 2020
Online course to train medical pros on use of mechanical ventilators
This week, Harvard and EdX, the virtual learning platform founded by Harvard and MIT, announced the launch of a free online course
designed to train frontline medical professionals to operate the
mechanical ventilators needed to treat COVID-19 patients. The class was
developed by Susan Wilcox, the division chief of critical care at
Massachusetts General Hospital (MGH) and an associate professor of
emergency medicine at Harvard Medical School, and Thomas Piraino,
clinical specialist for mechanical ventilation for the Centre of
Excellence in Mechanical Ventilation at St. Michael’s Hospital in
Toronto. The Gazette spoke with Wilcox about the genesis of her project
and how it will work.
GAZETTE: Clearly there’s a need for this kind of course now, as more and more medical professionals are called to help battle the COVID-19 pandemic. Is that what motivated you to put this course together?
WILCOX: I’ve been interested in teaching mechanical ventilation to groups that historically have not managed it for years. The principles are relatively straightforward, but mechanical ventilation is actually one of the most important things that we do when we’re taking care of critically ill patients. I’ve long thought that if we could encourage people to be more invested in managing ventilated patients, we could improve outcomes. I wrote a textbook about mechanical ventilation with a couple of colleagues from the Emergency Department a couple of years ago now, and with COVID-19 becoming a ventilator crisis, I distributed a version of that text widely on the internet. I was approached then by [the philanthropic organization] Schmidt Futures, which was looking to create a course on mechanical ventilation education for the masses, and they wanted to know if I wanted to collaborate. So, I can’t take credit for having the idea of creating the course: They came to me.
GAZETTE: How were you able to create this so quickly?
WILCOX: Normally, we’d spend three to six months putting together a course like this, but obviously, with the rapid spread of COVID-19, we don’t have that kind of time. As we move forward, we look forward to continuing to improve the course based on feedback from participants, and also as we learn more about this novel coronavirus.
GAZETTE: We’ve heard a lot about the need for ventilators to treat many of those individuals who are hospitalized with COVID-19. Why are these machines so important in battling this pandemic?
WILCOX: The predominant pathology of COVID-19 really seems to be profound respiratory failure. Patients are coming in with extremely low oxygen levels, and it’s clear that either the virus or the immune response to the virus is causing significant damage to portions of the lung and causing the little blood vessels inside the lung to be damaged. To treat that, we have to make sure that we give people sufficient support until their bodies are able to heal and fight the virus off. The good news about this is that, as is the case with most other critically ill patients who come to us with respiratory failure, low tidal volume, low-pressure ventilation does seem to be the best way to protect these patients’ lungs and give them the time they need to fight the virus off.
GAZETTE: How long do most patients need to be on them?
WILCOX: We are recognizing that it takes a really long time to defeat COVID-19; that the patients who are on the ventilators are requiring 10 to 14 days. Every disease is different, but we usually think of four to five days on ventilators as being a common length for many of the conditions that we see.
GAZETTE: Is that part of the reason why many communities seem to be experiencing a shortage of equipment during this pandemic?
WILCOX: I’m very confident in the care that we can provide at MGH. We are lucky in that we still have the resources to be able to serve the growing number of patients we see with this virus every day, and this number is definitely growing, day to day. And yes, what we need as a health care community is time. This is exactly the concept behind the flatten-the-curve initiative. Even if we have the same number of patients over the course of the entire pandemic, as long as we can prevent the health care system from being overwhelmed at various points throughout, I’m optimistic we can get many patients through this.
GAZETTE: Who is normally trained to use these machines, and who is using them now?
WILCOX: Normally, the people who manage mechanically ventilated patients are predominantly intensivists, or physicians who have done additional specific training in critical-care medicine. These doctors work in close collaboration with respiratory therapists, who are highly trained medical professionals who focus very specifically on taking care of patients with respiratory disorders. Traditionally, an intensivist and a respiratory therapist will collaborate on providing care to mechanically ventilated patients. And while a lot of doctors may get exposure to taking care of ventilated patients during their residencies, these experiences are usually fairly brief. If they don’t go on to specialize in critical care or anesthesiology, they’re unlikely to have seen a mechanically ventilated patient in quite some time. Even in the Emergency Department, while emergency physicians frequently intubate patients and put them on the ventilator, the in-depth management of the ventilator has not traditionally been a large focus of Emergency Medicine practice.
GAZETTE: How are things changing in emergency rooms and intensive-care units across the country with regard to who is providing care with ventilators?
WILCOX: The rising numbers of individuals we’re seeing with COVID-19 means that we now must bring in nurses and physicians who are highly trained in other areas to take care of ventilated patients. We’re fortunate that at MGH, we’re still able to, for now, have these nurses and physicians collaborate with those medical professionals who provide care through mechanical ventilation on a frequent basis. Of course, it certainly behooves these medical professionals to have some working understanding of mechanical ventilation going in, and that is part of the impetus behind creating this course.
GAZETTE: Tell us more about the course itself.
WILCOX: It’s important to say that first off that it’s not going to turn anyone into an intensivist or a respiratory therapist; it’s rather to give people foundational knowledge to be able to collaborate with one of these medical professionals who regularly works with mechanical ventilation. The course is made up of 10 different sections. It begins with the basics—an intro to the physiology of mechanically ventilated patients and to the ventilator in and of itself. It then moves into more advanced topics that go into in-depth rationale of what we do with the ventilator, while providing particular scenarios that could occur. We cover topics like management of acute respiratory distress syndrome, or ARDS, which is the major pathophysiology behind COVID-19. And we have a specific COVID-19 module, which covers mostly mechanical ventilation, but also other medical management of the condition. Each course is made up of 12 to 20 minutes of video depending on content, along with more in-depth readings. The video is fairly dynamic, with lots of illustrations and graphics to drive home points and to emphasize clinical decision-making. The writings get more into theory and in-depth background for learners who want to more fully understand the concepts.
GAZETTE: You said that you hope to continue to improve the course as you move forward. Can you explain more about your vision for doing this?
WILCOX: Normally, when we talk about research and studying medical conditions, it’s a many-months-to-many-years process. We will do studies that go through peer review, and we make sure we have all of our facts straight before anything gets published. Clearly with the rapid pace of this pandemic, that’s just not practical. We need to get information to people as quickly as we can. Some of the controversies right now with regard to mechanical ventilation and COVID-19 involve exactly when we should be putting people on the ventilators, as well as some of the details on how we should be optimizing these machines for patients. Since we’ve only seen patients with COVID-19 for about three weeks now in earnest at the time of this interview, we only have three weeks of data. In terms of the medical literature that’s nothing, so we’re doing the very best we can for all of these patients. With time we are going to better understand how we can improve their care, and we want to be able to communicate these learnings to those individuals who are taking this class.
GAZETTE: What have your days been like over the past few weeks?
WILCOX: I’m in a similar position to so many of my colleagues. We go to the hospital and see the hospital full of critically ill patients, and we work really hard to resuscitate all of them and give them the best care that we can. Then we all come home and then we go right back to work trying to read what our colleagues are publishing about this condition, or trying to write new protocols so we can stay up to date with the best literature. Many of us are finding we have extremely long workdays just trying to keep up with everything that’s going on. I’m not complaining; I’m very glad to be able to help. It’s just the reality of these times. We’re lucky to have so many people working really hard to battle this pandemic on every front.
https://medicalxpress.com/news/2020-04-online-medical-pros-mechanical-ventilators.html
GAZETTE: Clearly there’s a need for this kind of course now, as more and more medical professionals are called to help battle the COVID-19 pandemic. Is that what motivated you to put this course together?
WILCOX: I’ve been interested in teaching mechanical ventilation to groups that historically have not managed it for years. The principles are relatively straightforward, but mechanical ventilation is actually one of the most important things that we do when we’re taking care of critically ill patients. I’ve long thought that if we could encourage people to be more invested in managing ventilated patients, we could improve outcomes. I wrote a textbook about mechanical ventilation with a couple of colleagues from the Emergency Department a couple of years ago now, and with COVID-19 becoming a ventilator crisis, I distributed a version of that text widely on the internet. I was approached then by [the philanthropic organization] Schmidt Futures, which was looking to create a course on mechanical ventilation education for the masses, and they wanted to know if I wanted to collaborate. So, I can’t take credit for having the idea of creating the course: They came to me.
GAZETTE: How were you able to create this so quickly?
WILCOX: Normally, we’d spend three to six months putting together a course like this, but obviously, with the rapid spread of COVID-19, we don’t have that kind of time. As we move forward, we look forward to continuing to improve the course based on feedback from participants, and also as we learn more about this novel coronavirus.
GAZETTE: We’ve heard a lot about the need for ventilators to treat many of those individuals who are hospitalized with COVID-19. Why are these machines so important in battling this pandemic?
WILCOX: The predominant pathology of COVID-19 really seems to be profound respiratory failure. Patients are coming in with extremely low oxygen levels, and it’s clear that either the virus or the immune response to the virus is causing significant damage to portions of the lung and causing the little blood vessels inside the lung to be damaged. To treat that, we have to make sure that we give people sufficient support until their bodies are able to heal and fight the virus off. The good news about this is that, as is the case with most other critically ill patients who come to us with respiratory failure, low tidal volume, low-pressure ventilation does seem to be the best way to protect these patients’ lungs and give them the time they need to fight the virus off.
GAZETTE: How long do most patients need to be on them?
WILCOX: We are recognizing that it takes a really long time to defeat COVID-19; that the patients who are on the ventilators are requiring 10 to 14 days. Every disease is different, but we usually think of four to five days on ventilators as being a common length for many of the conditions that we see.
GAZETTE: Is that part of the reason why many communities seem to be experiencing a shortage of equipment during this pandemic?
WILCOX: I’m very confident in the care that we can provide at MGH. We are lucky in that we still have the resources to be able to serve the growing number of patients we see with this virus every day, and this number is definitely growing, day to day. And yes, what we need as a health care community is time. This is exactly the concept behind the flatten-the-curve initiative. Even if we have the same number of patients over the course of the entire pandemic, as long as we can prevent the health care system from being overwhelmed at various points throughout, I’m optimistic we can get many patients through this.
GAZETTE: Who is normally trained to use these machines, and who is using them now?
WILCOX: Normally, the people who manage mechanically ventilated patients are predominantly intensivists, or physicians who have done additional specific training in critical-care medicine. These doctors work in close collaboration with respiratory therapists, who are highly trained medical professionals who focus very specifically on taking care of patients with respiratory disorders. Traditionally, an intensivist and a respiratory therapist will collaborate on providing care to mechanically ventilated patients. And while a lot of doctors may get exposure to taking care of ventilated patients during their residencies, these experiences are usually fairly brief. If they don’t go on to specialize in critical care or anesthesiology, they’re unlikely to have seen a mechanically ventilated patient in quite some time. Even in the Emergency Department, while emergency physicians frequently intubate patients and put them on the ventilator, the in-depth management of the ventilator has not traditionally been a large focus of Emergency Medicine practice.
GAZETTE: How are things changing in emergency rooms and intensive-care units across the country with regard to who is providing care with ventilators?
WILCOX: The rising numbers of individuals we’re seeing with COVID-19 means that we now must bring in nurses and physicians who are highly trained in other areas to take care of ventilated patients. We’re fortunate that at MGH, we’re still able to, for now, have these nurses and physicians collaborate with those medical professionals who provide care through mechanical ventilation on a frequent basis. Of course, it certainly behooves these medical professionals to have some working understanding of mechanical ventilation going in, and that is part of the impetus behind creating this course.
GAZETTE: Tell us more about the course itself.
WILCOX: It’s important to say that first off that it’s not going to turn anyone into an intensivist or a respiratory therapist; it’s rather to give people foundational knowledge to be able to collaborate with one of these medical professionals who regularly works with mechanical ventilation. The course is made up of 10 different sections. It begins with the basics—an intro to the physiology of mechanically ventilated patients and to the ventilator in and of itself. It then moves into more advanced topics that go into in-depth rationale of what we do with the ventilator, while providing particular scenarios that could occur. We cover topics like management of acute respiratory distress syndrome, or ARDS, which is the major pathophysiology behind COVID-19. And we have a specific COVID-19 module, which covers mostly mechanical ventilation, but also other medical management of the condition. Each course is made up of 12 to 20 minutes of video depending on content, along with more in-depth readings. The video is fairly dynamic, with lots of illustrations and graphics to drive home points and to emphasize clinical decision-making. The writings get more into theory and in-depth background for learners who want to more fully understand the concepts.
GAZETTE: You said that you hope to continue to improve the course as you move forward. Can you explain more about your vision for doing this?
WILCOX: Normally, when we talk about research and studying medical conditions, it’s a many-months-to-many-years process. We will do studies that go through peer review, and we make sure we have all of our facts straight before anything gets published. Clearly with the rapid pace of this pandemic, that’s just not practical. We need to get information to people as quickly as we can. Some of the controversies right now with regard to mechanical ventilation and COVID-19 involve exactly when we should be putting people on the ventilators, as well as some of the details on how we should be optimizing these machines for patients. Since we’ve only seen patients with COVID-19 for about three weeks now in earnest at the time of this interview, we only have three weeks of data. In terms of the medical literature that’s nothing, so we’re doing the very best we can for all of these patients. With time we are going to better understand how we can improve their care, and we want to be able to communicate these learnings to those individuals who are taking this class.
GAZETTE: What have your days been like over the past few weeks?
WILCOX: I’m in a similar position to so many of my colleagues. We go to the hospital and see the hospital full of critically ill patients, and we work really hard to resuscitate all of them and give them the best care that we can. Then we all come home and then we go right back to work trying to read what our colleagues are publishing about this condition, or trying to write new protocols so we can stay up to date with the best literature. Many of us are finding we have extremely long workdays just trying to keep up with everything that’s going on. I’m not complaining; I’m very glad to be able to help. It’s just the reality of these times. We’re lucky to have so many people working really hard to battle this pandemic on every front.
https://medicalxpress.com/news/2020-04-online-medical-pros-mechanical-ventilators.html
How a new vaccine adjuvant might shorten race to COVID-19 immunity
Uli von Andrian is the Mallinckrodt Professor of Immunopathology at
Harvard Medical School and Program Leader of Basic Immunology at the
Ragon Institute of MGH, MIT, and Harvard.
In an interview with the Harvard Office of Technology Development (OTD), von Andrian suggests that further research and development on a class of molecules called bisphosphonates might turbocharge a vaccine against SARS-CoV-2, the novel coronavirus, and help bring immunity to huge populations more quickly.
OTD: Hopefully, the first COVID-19 vaccines will be approved in the coming year or so, and the demand will be overwhelming. One of the challenges will be making enough doses to ensure herd immunity. How does your work address this challenge?
VON ANDRIAN: I remember when the swine flu hit the world. It turned out to be, fortunately, much less virulent than what we’re experiencing now. There was a vaccine developed relatively quickly. This was a flu virus, so there was a lot of technology already in place to make a vaccine for it. But I recall my kids and I trying to get this vaccine at the local high school. By the time we got there, there was already a line of people for a block and a half. And we actually never made it into the school, because they ran out of the vaccine way before it would have been our turn.
And I think the COVID-19 situation is at a completely different scale.
There are multiple vaccine candidates that all have one goal, I think, which is to enable patients to make neutralizing antibodies against a surface structure on the virus, the spike protein, which is composed of two subunits. The virus uses its spike to dock onto a target cell in a host and infect that cell. You can imagine, if you could gum this up with an antibody, this would prevent the virus from getting into the host cell. I think that idea is justified, because there are many other related coronavirus viruses where antibodies that target specific regions of the spike have been shown to be neutralizing.
OTD: So what’s the catch?
VON ANDRIAN: Well, there are multiple copies of this spike or protein on every single virus. So you need to make enough antibodies at sufficiently high affinity to detect and neutralize all of these spike proteins before the virus has a chance to get into a cell. The catch is that if you vaccinate someone and they start to make antibodies, it will take a while, often more than a month, to actually confer meaningful protection.
OTD: During an ongoing outbreak of disease, the need is more urgent. How can we speed it up?
VON ANDRIAN: We get help from adjuvants.
Imagine all the bacteria that live on our various surfaces that are completely innocuous. If we were to mount vigorous immune responses against every single one of those, our immune system would be completely overwhelmed. A lot of structures are molecularly boring to us and while they’re detected by the immune system, most of them are just ignored or tolerated, and for good reason.
If you have a misguided immune response against something that you should be tolerant to, you can get inflammatory diseases or allergies. So it’s important when you make a vaccine that the vaccine is provided in the proper context. It says, “Here’s a foreign structure, you actually need to pay attention to it, and this is the kind of immune response that you should raise against it.” This context is usually provided by what we call adjuvants, additives to the vaccine. Adjuvants can have very different chemical compositions, including lipids, proteins, nucleic acids, and even inorganic material, such as aluminum salt. They all have in common that they stimulate sensors in immune cells that are usually triggered by microbial infections or tissue damage.
So you can just say, “Watch out, it’s dangerous,” or you can yell at someone at the top of your lungs, “It’s dangerous!” And the response you will elicit will be different. The same can be said about the potency of adjuvants. The immune response you get will also differ, in terms of quantity and in terms of quality. Different adjuvants also trigger different sensing pathways in our immune system.
When you choose your vaccine antigens, you need to combine them with a sufficient danger signal.
OTD: So adjuvants are already used in vaccines. Does that not solve the problem for vaccines against the novel coronavirus?
VON ANDRIAN: There are a few promising vaccine candidates at the moment, including an mRNA vaccine and the work of Daniel Barouch at Beth Israel using adenoviral vectors, as well as others. But in most cases, you still have to wait weeks. The current trial for an mRNA vaccine, for instance, calls for a prime-boost protocol. That means you actually give the antigen, or the vaccine, twice, in a one-month interval.
The first time around, you alert the immune system. But in many cases, and that’s true for many other classic vaccines too, the response is not vigorous enough for long-lasting immunity to occur. You have to wait several weeks, and then this booster shot gives you the really vigorous antibody response that is much more longer lasting and of much greater quality. And then it’s typically yet another two weeks or so before you actually have protection.
So, whenever that vaccine is available, if you have to do to the prime-boost regimen before you get protection, you have to actually add another month and a half or so, on top of the date of the availability of the vaccine. So that’s what we can look forward to right now.
OTD: But you’ve made some important discoveries and innovations that could change the way vaccines are formulated.
VON ANDRIAN: Yes. We published it seven years ago, and we made the observation probably 10 years ago, that there’s a class of drugs called bisphosphonates that have some interesting adjuvant-like properties that were completely unexpected. This is what I think we should be looking into.
OTD: OK, walk us through it. What are these bisphosphonates, and how did you figure out they were useful here?
VON ANDRIAN: So these are small molecules, relatively simple drugs, actually, and widely used in the clinic. The first bisphosphonate was approved by the FDA in 1979 to prevent bone loss. There’s a whole family of small molecules that all have the classic core structure with two phosphorous groups. These are all very old drugs, so they’re generics, which means they are cheap and they’re widely available. One of the clinical uses is osteoporosis, because the osteoclasts that eat and destroy bone are selectively killed by this drug.
But bisphosphonates are also used experimentally in mouse immunology. You can package a bisphosphonate called Clodronate into a liposome—basically a tiny lipid bubble. To immune cells, to macrophages, they look just like a virus. But they kill off the macrophages, which lets you study the function of these cells in various disease models. It’s very useful.
We were using these in my lab, and what we observed is that there’s a very specialized population of macrophages that live in the lymph nodes and initiate an immune response. These special macrophages capture viruses and present them to the B-cells so they can make antibodies. We published that in 2007. And we thought that if you deplete those macrophages with Clodronate liposomes, then it should have a negative effect on the mouse immune response.
But we were really surprised to see that the opposite happened. The immune response against the virus produced an antibody titer that was up to 100-fold greater compared to the control group. So that was weird. It suggested that maybe our findings were incorrect or our interpretation was not correct, and that actually these macrophages have the opposite function of what we had seen and what we had published. That troubled us a great deal.
It turned out that macrophages actually had nothing to do with it. When we gave Clodronate in free-form, which doesn’t deplete this group of macrophages, we actually saw the same dramatic effect on antibody responses.
Then, we said, aha, if this happens with Clodronate, perhaps it’s true for all the bisphosphonates. And so we tried several. And indeed, that’s what we saw. Each of the bisphosphonates we tested had this massive adjuvant-like effect, where the antibody response was much higher, but it was also much faster. We saw neutralizing antibody activity within just five days, at least for this Vesicular Stomatitis Virus that we were testing—very fast, after a single exposure.
So then we tried to figure out how this worked. We did a whole bunch of experiments that are described in this paper we published in 2013, which says that actually bisphosphonates have this additional and completely different mechanism of action.
OTD: In what way?
VON ANDRIAN: They do not work like any of the traditional adjuvants, but they seem to have a direct effect on B cells. For that reason, I think that they are really interesting. Because if you have an existing vaccine that already has an adjuvant that may be active, but perhaps weak, if you combine it with a bisphosphonate, you would expect to see synergistic activity. In fact, we tried bisphosphonate in combination with readily available vaccines, and we saw, indeed, that there was an amplification of the antibody immune response to those vaccines.
What we are now trying to explore in animal models is, could we basically use bisphosphonate to turbocharge whatever COVID-19 vaccines may come online, hopefully within a year or so.
OTD: In practical terms, how do you see it potentially improving the outcomes of vaccination?
VON ANDRIAN: The hope would be that by combining the vaccine with a bisphosphonate, you might need less vaccine per person. That means that if there’s a finite quantity that can be produced per unit time, you might be able to vaccinate more people. The second possibility is, by adding a bisphosphonate, perhaps a prime is enough and you don’t need a booster. So you could get much faster protection with less material.
OTD: That seems like it’s going to be so important if we want people to be able to return to normal life, or something like it.
VON ANDRIAN: Yes, absolutely, right. I’m hopeful. There’s quite a bit of information on bisphosphonate in humans. As far as I’m aware, I haven’t seen anything where people have looked specifically at immune responses, except actually in our own paper in 2013, but I think it’s really intriguing. And so personally, I would like to see bisphosphonate tested prior to the arrival of a vaccine.
OTD: What needs to happen next with this? Is the aim to move it into clinical trials? Who else needs to get involved in that effort?
VON ANDRIAN: I think to compel clinicians and regulatory agencies to agree to let us test this, I think we first need to do some more specific experiments with COVID-19 vaccines and with COVID-19 infection.
I have a subgroup of members of my lab who got special permission by the dean to actually go into the lab and do these experiments. Everyone else is supposed to stay at home. We have started to look at a few questions. The first one is to determine whether we can demonstrate in the lab that treatment for viral pneumonia with bisphosphonate is beneficial in mice. If so, what is the optimal dosing regimen? This is really important. Normally, bisphosphonates are used chronically over years. That’s not what we are talking about. We have to elucidate all these questions in animals first.
And then we’ve actually ordered several different bisphosphonates. They’re different in their chemistry and they’re different in how they’re administered. We’d like to compare them to see if one stands out as being particularly potent. That’s another important question.
Then separately and in parallel, we can address another question. If we immunize animal models at doses that are deliberately insufficient to elicit the maximum response, does the addition of the bisphosphonate give us an immune response that is equivalent to, or maybe better than the response to the vaccine alone at a higher dose?
And then what’s the quality and longevity of the immune response; what’s the onset of the immune response? In other words, can we replicate in primates what we’ve seen in mice? We will have to start in mice with the COVID-19 vaccine.
OTD: You mentioned that bisphosphonates have been around for a long time. Does that confer any advantage, given the urgency of these efforts?
VON ANDRIAN: That’s one of the beauties of this. They’re widely available and they’re generic, so they’re cheap. And they are already approved for clinical use. That’s actually very important, because there is no adjuvant that is approved anywhere as an adjuvant alone. There are only vaccines, where the vaccine is a combination of antigens plus an adjuvant. So that means if you have a candidate vaccine, it is what it is. You cannot just simply say, OK, as of today, I’m going to add a different adjuvant to it—unless there’s a drug that’s already approved for something else and, as the prescribing physician, you can use it off-label.
OTD: Are there certain collaborations that your lab group needs to build to make this happen?
VON ANDRIAN: Within my own group, I have very good people; they’re very experienced and eager to do this basic research. But as we move this along to other species, it will become extremely expensive. Then also, in particular, to take this from animals into the clinic will require expertise that others have much more than we do.
Being able to communicate and collaborate with all of the amazing members of our community is going to be absolutely critical to very rapidly move this out of the lab and into the clinic. That’s what we all hope for as scientists, right? In some way, you make a difference. And this would be, obviously, a wonderful way to contribute to this.
There’s so much at stake. And there are so many people that are going to suffer a great deal. I think as a member of humankind, you have an obligation to do what you can to deal with this in any way possible.
https://medicalxpress.com/news/2020-04-vaccine-adjuvant-shorten-covid-immunity.html
In an interview with the Harvard Office of Technology Development (OTD), von Andrian suggests that further research and development on a class of molecules called bisphosphonates might turbocharge a vaccine against SARS-CoV-2, the novel coronavirus, and help bring immunity to huge populations more quickly.
OTD: Hopefully, the first COVID-19 vaccines will be approved in the coming year or so, and the demand will be overwhelming. One of the challenges will be making enough doses to ensure herd immunity. How does your work address this challenge?
VON ANDRIAN: I remember when the swine flu hit the world. It turned out to be, fortunately, much less virulent than what we’re experiencing now. There was a vaccine developed relatively quickly. This was a flu virus, so there was a lot of technology already in place to make a vaccine for it. But I recall my kids and I trying to get this vaccine at the local high school. By the time we got there, there was already a line of people for a block and a half. And we actually never made it into the school, because they ran out of the vaccine way before it would have been our turn.
And I think the COVID-19 situation is at a completely different scale.
There are multiple vaccine candidates that all have one goal, I think, which is to enable patients to make neutralizing antibodies against a surface structure on the virus, the spike protein, which is composed of two subunits. The virus uses its spike to dock onto a target cell in a host and infect that cell. You can imagine, if you could gum this up with an antibody, this would prevent the virus from getting into the host cell. I think that idea is justified, because there are many other related coronavirus viruses where antibodies that target specific regions of the spike have been shown to be neutralizing.
OTD: So what’s the catch?
VON ANDRIAN: Well, there are multiple copies of this spike or protein on every single virus. So you need to make enough antibodies at sufficiently high affinity to detect and neutralize all of these spike proteins before the virus has a chance to get into a cell. The catch is that if you vaccinate someone and they start to make antibodies, it will take a while, often more than a month, to actually confer meaningful protection.
OTD: During an ongoing outbreak of disease, the need is more urgent. How can we speed it up?
VON ANDRIAN: We get help from adjuvants.
Imagine all the bacteria that live on our various surfaces that are completely innocuous. If we were to mount vigorous immune responses against every single one of those, our immune system would be completely overwhelmed. A lot of structures are molecularly boring to us and while they’re detected by the immune system, most of them are just ignored or tolerated, and for good reason.
If you have a misguided immune response against something that you should be tolerant to, you can get inflammatory diseases or allergies. So it’s important when you make a vaccine that the vaccine is provided in the proper context. It says, “Here’s a foreign structure, you actually need to pay attention to it, and this is the kind of immune response that you should raise against it.” This context is usually provided by what we call adjuvants, additives to the vaccine. Adjuvants can have very different chemical compositions, including lipids, proteins, nucleic acids, and even inorganic material, such as aluminum salt. They all have in common that they stimulate sensors in immune cells that are usually triggered by microbial infections or tissue damage.
So you can just say, “Watch out, it’s dangerous,” or you can yell at someone at the top of your lungs, “It’s dangerous!” And the response you will elicit will be different. The same can be said about the potency of adjuvants. The immune response you get will also differ, in terms of quantity and in terms of quality. Different adjuvants also trigger different sensing pathways in our immune system.
When you choose your vaccine antigens, you need to combine them with a sufficient danger signal.
OTD: So adjuvants are already used in vaccines. Does that not solve the problem for vaccines against the novel coronavirus?
VON ANDRIAN: There are a few promising vaccine candidates at the moment, including an mRNA vaccine and the work of Daniel Barouch at Beth Israel using adenoviral vectors, as well as others. But in most cases, you still have to wait weeks. The current trial for an mRNA vaccine, for instance, calls for a prime-boost protocol. That means you actually give the antigen, or the vaccine, twice, in a one-month interval.
The first time around, you alert the immune system. But in many cases, and that’s true for many other classic vaccines too, the response is not vigorous enough for long-lasting immunity to occur. You have to wait several weeks, and then this booster shot gives you the really vigorous antibody response that is much more longer lasting and of much greater quality. And then it’s typically yet another two weeks or so before you actually have protection.
So, whenever that vaccine is available, if you have to do to the prime-boost regimen before you get protection, you have to actually add another month and a half or so, on top of the date of the availability of the vaccine. So that’s what we can look forward to right now.
OTD: But you’ve made some important discoveries and innovations that could change the way vaccines are formulated.
VON ANDRIAN: Yes. We published it seven years ago, and we made the observation probably 10 years ago, that there’s a class of drugs called bisphosphonates that have some interesting adjuvant-like properties that were completely unexpected. This is what I think we should be looking into.
OTD: OK, walk us through it. What are these bisphosphonates, and how did you figure out they were useful here?
VON ANDRIAN: So these are small molecules, relatively simple drugs, actually, and widely used in the clinic. The first bisphosphonate was approved by the FDA in 1979 to prevent bone loss. There’s a whole family of small molecules that all have the classic core structure with two phosphorous groups. These are all very old drugs, so they’re generics, which means they are cheap and they’re widely available. One of the clinical uses is osteoporosis, because the osteoclasts that eat and destroy bone are selectively killed by this drug.
But bisphosphonates are also used experimentally in mouse immunology. You can package a bisphosphonate called Clodronate into a liposome—basically a tiny lipid bubble. To immune cells, to macrophages, they look just like a virus. But they kill off the macrophages, which lets you study the function of these cells in various disease models. It’s very useful.
We were using these in my lab, and what we observed is that there’s a very specialized population of macrophages that live in the lymph nodes and initiate an immune response. These special macrophages capture viruses and present them to the B-cells so they can make antibodies. We published that in 2007. And we thought that if you deplete those macrophages with Clodronate liposomes, then it should have a negative effect on the mouse immune response.
But we were really surprised to see that the opposite happened. The immune response against the virus produced an antibody titer that was up to 100-fold greater compared to the control group. So that was weird. It suggested that maybe our findings were incorrect or our interpretation was not correct, and that actually these macrophages have the opposite function of what we had seen and what we had published. That troubled us a great deal.
It turned out that macrophages actually had nothing to do with it. When we gave Clodronate in free-form, which doesn’t deplete this group of macrophages, we actually saw the same dramatic effect on antibody responses.
Then, we said, aha, if this happens with Clodronate, perhaps it’s true for all the bisphosphonates. And so we tried several. And indeed, that’s what we saw. Each of the bisphosphonates we tested had this massive adjuvant-like effect, where the antibody response was much higher, but it was also much faster. We saw neutralizing antibody activity within just five days, at least for this Vesicular Stomatitis Virus that we were testing—very fast, after a single exposure.
So then we tried to figure out how this worked. We did a whole bunch of experiments that are described in this paper we published in 2013, which says that actually bisphosphonates have this additional and completely different mechanism of action.
OTD: In what way?
VON ANDRIAN: They do not work like any of the traditional adjuvants, but they seem to have a direct effect on B cells. For that reason, I think that they are really interesting. Because if you have an existing vaccine that already has an adjuvant that may be active, but perhaps weak, if you combine it with a bisphosphonate, you would expect to see synergistic activity. In fact, we tried bisphosphonate in combination with readily available vaccines, and we saw, indeed, that there was an amplification of the antibody immune response to those vaccines.
What we are now trying to explore in animal models is, could we basically use bisphosphonate to turbocharge whatever COVID-19 vaccines may come online, hopefully within a year or so.
OTD: In practical terms, how do you see it potentially improving the outcomes of vaccination?
VON ANDRIAN: The hope would be that by combining the vaccine with a bisphosphonate, you might need less vaccine per person. That means that if there’s a finite quantity that can be produced per unit time, you might be able to vaccinate more people. The second possibility is, by adding a bisphosphonate, perhaps a prime is enough and you don’t need a booster. So you could get much faster protection with less material.
OTD: That seems like it’s going to be so important if we want people to be able to return to normal life, or something like it.
VON ANDRIAN: Yes, absolutely, right. I’m hopeful. There’s quite a bit of information on bisphosphonate in humans. As far as I’m aware, I haven’t seen anything where people have looked specifically at immune responses, except actually in our own paper in 2013, but I think it’s really intriguing. And so personally, I would like to see bisphosphonate tested prior to the arrival of a vaccine.
OTD: What needs to happen next with this? Is the aim to move it into clinical trials? Who else needs to get involved in that effort?
VON ANDRIAN: I think to compel clinicians and regulatory agencies to agree to let us test this, I think we first need to do some more specific experiments with COVID-19 vaccines and with COVID-19 infection.
I have a subgroup of members of my lab who got special permission by the dean to actually go into the lab and do these experiments. Everyone else is supposed to stay at home. We have started to look at a few questions. The first one is to determine whether we can demonstrate in the lab that treatment for viral pneumonia with bisphosphonate is beneficial in mice. If so, what is the optimal dosing regimen? This is really important. Normally, bisphosphonates are used chronically over years. That’s not what we are talking about. We have to elucidate all these questions in animals first.
And then we’ve actually ordered several different bisphosphonates. They’re different in their chemistry and they’re different in how they’re administered. We’d like to compare them to see if one stands out as being particularly potent. That’s another important question.
Then separately and in parallel, we can address another question. If we immunize animal models at doses that are deliberately insufficient to elicit the maximum response, does the addition of the bisphosphonate give us an immune response that is equivalent to, or maybe better than the response to the vaccine alone at a higher dose?
And then what’s the quality and longevity of the immune response; what’s the onset of the immune response? In other words, can we replicate in primates what we’ve seen in mice? We will have to start in mice with the COVID-19 vaccine.
OTD: You mentioned that bisphosphonates have been around for a long time. Does that confer any advantage, given the urgency of these efforts?
VON ANDRIAN: That’s one of the beauties of this. They’re widely available and they’re generic, so they’re cheap. And they are already approved for clinical use. That’s actually very important, because there is no adjuvant that is approved anywhere as an adjuvant alone. There are only vaccines, where the vaccine is a combination of antigens plus an adjuvant. So that means if you have a candidate vaccine, it is what it is. You cannot just simply say, OK, as of today, I’m going to add a different adjuvant to it—unless there’s a drug that’s already approved for something else and, as the prescribing physician, you can use it off-label.
OTD: Are there certain collaborations that your lab group needs to build to make this happen?
VON ANDRIAN: Within my own group, I have very good people; they’re very experienced and eager to do this basic research. But as we move this along to other species, it will become extremely expensive. Then also, in particular, to take this from animals into the clinic will require expertise that others have much more than we do.
Being able to communicate and collaborate with all of the amazing members of our community is going to be absolutely critical to very rapidly move this out of the lab and into the clinic. That’s what we all hope for as scientists, right? In some way, you make a difference. And this would be, obviously, a wonderful way to contribute to this.
There’s so much at stake. And there are so many people that are going to suffer a great deal. I think as a member of humankind, you have an obligation to do what you can to deal with this in any way possible.
https://medicalxpress.com/news/2020-04-vaccine-adjuvant-shorten-covid-immunity.html
Cats far more susceptible to Covid-19 than dogs, but don’t be ‘fearful’ of pets
If your cat is being socially distant these days, maybe he’s just trying to protect both of you.
A Chinese study published Wednesday in the journal Science reported that tests of the new coronavirus on domesticated cats, dogs, pigs, chickens, ducks and ferrets found that both cats and ferrets are highly susceptible to the virus. Cats can become infected through airborne transmission. Dogs, however, have a very low susceptibility to the virus.
Susceptibility means that a virus is able to enter a cell.
Specialists in veterinary medicine stressed that the study included very small numbers of cats and dogs, which were injected with much higher levels of the new coronavirus than they would likely encounter in the natural world. They also said it is highly unlikely that a person would become infected from a pet.
“I don’t think that for most people cat-to-human transmission is the most likely way that they would be infected, but I’d be very surprised if this was impossible,” said David O’Connor, a professor of pathology and laboratory medicine at the University of Wisconsin-Madison.
“This is a human disease,” said Jeanette O’Quin, an assistant professor in the Department of Veterinary Preventive Medicine at Ohio State University. “It’s being transferred from person to person. That is our greatest risk.”
Still, the new paper follows a scattering of reports of animals becoming infected with the new coronavirus. Less than a week ago the Bronx Zoo announced that a 4-year-old Malayan tiger, named Nadia, tested positive for COVID-19.
A separate Chinese study reported that after the outbreak began in Wuhan, 14% of cats in the area were found to have antibodies for the virus, O’Connor said.
In Hong Kong, a recent study examined 17 dogs and eight cats taken from households where a human had become sick with COVID-19 or had come in close contact with a confirmed patient. In that group, two dogs tested positive, though one was deemed to be “a weak” positive. The cats were not positive at the most recent testing.
Jane Sykes, a professor of small animal medicine at the University of California, Davis School of Veterinary Medicine, cited a much larger report by a major veterinary laboratory, IDEXX, involving more than 4000 samples taken from dogs, cats and horses. None of the animals showed any evidence of the new coronavirus.
The samples were collected from animals in the U.S. and South Korea during a four-week period, starting on Feb. 14.
“There’s a lot of stress in the world and the human-animal bond is so important,” Sykes said. “We should be enjoying our pets, rather than being fearful of them.”
Sykes and O’Quin both recommended steps people can take to reduce the small risk of the virus passing between people and their pets.
Sykes said that people who have COVID-19 should probably keep the pet in another part of the house and have another person in the household care for it. If there is no one else to care for the pet, the infected person should wear a mask when caring for the pet and wash their hands before and after feeding the animal. She also advised people not to allow a pet to lick them in the mouth.
Although the risk of the virus passing between pets and people “is really low, we should take precautions,” O’Quin said.
If pet owners are quarantining themselves, they should also quarantine their cats inside.
“If you’re not sick,” O’Quin said, “you can interact with them pretty much the way you would always.”
With Bronx Zoo tiger catching coronavirus, should pet owners be concerned about COVID-19? Health experts weigh in
A Chinese study published Wednesday in the journal Science reported that tests of the new coronavirus on domesticated cats, dogs, pigs, chickens, ducks and ferrets found that both cats and ferrets are highly susceptible to the virus. Cats can become infected through airborne transmission. Dogs, however, have a very low susceptibility to the virus.
Susceptibility means that a virus is able to enter a cell.
Specialists in veterinary medicine stressed that the study included very small numbers of cats and dogs, which were injected with much higher levels of the new coronavirus than they would likely encounter in the natural world. They also said it is highly unlikely that a person would become infected from a pet.
“I don’t think that for most people cat-to-human transmission is the most likely way that they would be infected, but I’d be very surprised if this was impossible,” said David O’Connor, a professor of pathology and laboratory medicine at the University of Wisconsin-Madison.
“This is a human disease,” said Jeanette O’Quin, an assistant professor in the Department of Veterinary Preventive Medicine at Ohio State University. “It’s being transferred from person to person. That is our greatest risk.”
Still, the new paper follows a scattering of reports of animals becoming infected with the new coronavirus. Less than a week ago the Bronx Zoo announced that a 4-year-old Malayan tiger, named Nadia, tested positive for COVID-19.
A separate Chinese study reported that after the outbreak began in Wuhan, 14% of cats in the area were found to have antibodies for the virus, O’Connor said.
In Hong Kong, a recent study examined 17 dogs and eight cats taken from households where a human had become sick with COVID-19 or had come in close contact with a confirmed patient. In that group, two dogs tested positive, though one was deemed to be “a weak” positive. The cats were not positive at the most recent testing.
Jane Sykes, a professor of small animal medicine at the University of California, Davis School of Veterinary Medicine, cited a much larger report by a major veterinary laboratory, IDEXX, involving more than 4000 samples taken from dogs, cats and horses. None of the animals showed any evidence of the new coronavirus.
The samples were collected from animals in the U.S. and South Korea during a four-week period, starting on Feb. 14.
“There’s a lot of stress in the world and the human-animal bond is so important,” Sykes said. “We should be enjoying our pets, rather than being fearful of them.”
Sykes and O’Quin both recommended steps people can take to reduce the small risk of the virus passing between people and their pets.
Sykes said that people who have COVID-19 should probably keep the pet in another part of the house and have another person in the household care for it. If there is no one else to care for the pet, the infected person should wear a mask when caring for the pet and wash their hands before and after feeding the animal. She also advised people not to allow a pet to lick them in the mouth.
Although the risk of the virus passing between pets and people “is really low, we should take precautions,” O’Quin said.
If pet owners are quarantining themselves, they should also quarantine their cats inside.
“If you’re not sick,” O’Quin said, “you can interact with them pretty much the way you would always.”
Explore further
More information: Jianzhong Shi et al. Susceptibility of ferrets, cats, dogs, and other domesticated animals to SARS–coronavirus 2, Science (2020). DOI: 10.1126/science.abb7015
Expert reactions to a study looking at susceptibility of pets to the COVID-19 virus (SARS-CoV-2): https://www.sciencemediacentre.org/expert-reaction-to-a-study-looking-at-susceptibility-of-pets-to-the-covid-19-virus-sars-cov-2/
New signs suggest coronavirus was in California far earlier than anyone knew
A man found dead in his house in early March. A woman who fell sick in mid-February and later died.
These early COVID-19 deaths in the San Francisco Bay Area suggest that the novel coronavirus had established itself in the community long before health officials started looking for it. The lag time has had dire consequences, allowing the virus to spread unchecked before social distancing rules went into effect.
“The virus was freewheeling in our community and probably has been here for quite some time,” Dr. Jeff Smith, a physician who is the chief executive of Santa Clara County government, told county leaders in a recent briefing.
How long? A study out of Stanford suggests a dramatic viral surge in February.
But Smith on Friday said data collected by the federal Centers for Disease Control and Prevention, local health departments and others suggest it was “a lot longer than we first believed” — most likely since “back in December.”
“This wasn’t recognized because we were having a severe flu season,” Smith said in an interview. “Symptoms are very much like the flu. If you got a mild case of COVID, you didn’t really notice. You didn’t even go to the doctor. The doctor maybe didn’t even do it because they presumed it was the flu.”
Just as New York has strong ties to travelers from Europe, who are believed to have brought the coronavirus there from Italy, the Bay Area is a natural hub for those traveling to and from China. Santa Clara County had its first two cases of COVID-19 almost a week before federal approval of emergency testing for the disease Feb. 4. Both were in travelers returning from Wuhan, China, where the virus was rampant.
In January and most of February, there was little, if any, community testing in California.
The CDC provided testing materials to only some health departments, with restrictions that confined testing and thus the tracking of the novel coronavirus to those who were sick or exposed to someone already known to have COVID-19. The federal agency’s focus was on cruise ships, with Princess Cruises’ Diamond Princess carrying the largest known cluster of COVID-19 cases outside of China. The first passenger tested positive for COVID-19 five days after the ship’s Jan. 20 departure from Japan. Eventually, 712 passengers and crew tested positive, and nine of them died.
COVID-19 did not reappear in the Bay Area until Feb. 27, when doctors finally decided to test a hospitalized woman who had been ill for weeks. She became the region’s first case of community-spread coronavirus.
But from there, almost every positive test pointed toward local spread. “When public health [officials] tried to track down the start of the disease … we weren’t able to find, specifically, a contact,” Smith told county supervisors. “That means the virus is in the community already — not, as was suspected by the CDC, as only in China and being spread from contact with China.”
Researchers still unsure how long the virus lurked are now turning to blood banks and other repositories to see if lingering antibodies can show them what was missed. A study funded by the National Institutes of Health is looking for virus antibodies in samples from blood banks in Los Angeles, San Francisco and four other cities across the country.
Santa Clara County’s first community-spread case also became its first announced COVID-19 death.
Azar Ahrabi, 68, died March 9, the second COVID-19 fatality in California, five days after the first. For the first few weeks, the urban county that sits at the heart of Silicon Valley, home to Stanford University and tech giants Apple and Google, led California in coronavirus deaths.
Health investigators said they could find no source of Ahrabi’s infection. Her family members said she stayed mostly at home, taking care of her mother. She seldom drove, and she walked to a local grocery store to shop. But she and her mother lived in a Santa Clara apartment complex in a neighborhood with a high density of international residents.
Relatives said she showed signs of illness in mid-February. For more than a week, they gave only a passing thought that her fever and sudden fatigue might be tied to the horrifying news out of China.
Ahrabi’s son, Amir, said that when his mother checked into a medical clinic Feb. 20 and was diagnosed with a nonspecific pneumonia, she was prescribed antibiotics and sent home. The next day, her doctor admitted her to the intensive care unit.
Amir said he asked that she be tested for COVID-19, and doctors told him the county health department would not approve the test. She met none of the qualifying criteria.
New studies out of Stanford University and the CDC, taken together, suggest that the novel coronavirus spread quickly through the Bay Area.
Stanford’s virology lab, looking retroactively at some 2,800 patient samples collected since January, did not find the first COVID-19 cases until late February — from two patients who were tested Feb. 21 and Feb. 23. Neither of those patients, the researchers note in a letter published by the Journal of the American Medical Assn., would have met existing criteria for COVID-19 testing.
The California Department of Public Health and the CDC did not begin community surveillance for COVID-19 in Santa Clara County until March 5. Samples were collected from 226 coughing, feverish patients who visited four urgent care centers; 1 in 4 turned out to have the flu. The state tested samples from a subset of 79 non-flu patients. Nine of them had COVID-19.
The result suggested that 8% of people walking into the urgent care centers carried the novel coronavirus, an infection rate that mirrored the 5% infection rate at a Los Angeles medical center, the CDC said in a report published Friday.
It is possible the coronavirus spread widely through the Bay Area in
just two weeks, said Dr. Benjamin Pinsky, the pathologist who led the
Stanford study. He said Stanford’s virology clinic saw a similar
increase in cases once it was cleared by the federal government to begin
running its own COVID-19 tests.
Pinsky said the virtual invisibility of COVID-19 in February followed by an 8% infection rate two weeks later is not “incompatible…. I think that all kind of fits together.”
Santa Clara County acted on the CDC’s local sampling immediately. Two days after the project ended, it and five other Bay Area counties ordered residents to stay home and schools and nonessential businesses to close. Azar Ahrabi by then was dead.
Amir said he sees his mother as on the cruel side of history, falling ill before Californians were ready to look for the virus already in their presence. For his mother, that realization came too late.
The first confirmed COVID-19 death in California was March 4 in Placer County, claiming the life of a 71-year-old man who had recently taken a Mexican cruise. A ship medical officer told The Times the man had developed symptoms during the Feb. 11-21 voyage, suggesting he brought the virus on board from California.
Two days later, March 6, San Jose authorities found a 70-year-old man dead in his home. The Santa Clara County medical examiner determined the man tested positive for COVID-19, according to records provided to The Times. The discovery of this second death was never publicly announced, and county health officials did not answer questions about the case.
Research by The Times showed he lived less than four miles from Azar Ahrabi, essentially off the same main road with an interstate between them.
The diagnosis of Ahrabi appeared to the family to make little difference in her steady decline. She was put into an induced coma and intubated with a ventilator. Family members were not allowed to see her. The county put them in quarantine and served a legal order to back that up.
Physicians threw a slew of treatments at Ahrabi — including offering a controversial synthetic quinine used to treat malaria but using another experimental treatment, Remdesivir. But her liver failed, and her body rejected dialysis treatment. The ventilator could not deliver enough oxygen through her occluded lungs, and the hospital did not have a machine to infuse oxygen directly into her blood.
“She was essentially tested a week and a half after her first symptoms, and some of the treatments that were proposed and [that] we went with could have been way more effective if we — they — put them in place days ago,” Amir said.
Amir was ordered by Santa Clara County to go into quarantine the day his mother’s test result came back, and he never saw her alive again.
As she died, he stayed in his apartment with his grandmother, caring for the elderly woman without telling her the fate of her daughter. Only after the quarantine order was lifted, when the whole family could again gather, did they tell her Azar Ahrabi had died.
Iranian tradition dictated that the family wash her body and prepare it to eventually return to the earth, Amir said. Instead, the county health department required that she be sealed into a plastic bag for interment.
https://www.latimes.com/california/story/2020-04-11/bay-area-coronavirus-deaths-signs-of-earlier-spread-california
These early COVID-19 deaths in the San Francisco Bay Area suggest that the novel coronavirus had established itself in the community long before health officials started looking for it. The lag time has had dire consequences, allowing the virus to spread unchecked before social distancing rules went into effect.
“The virus was freewheeling in our community and probably has been here for quite some time,” Dr. Jeff Smith, a physician who is the chief executive of Santa Clara County government, told county leaders in a recent briefing.
How long? A study out of Stanford suggests a dramatic viral surge in February.
But Smith on Friday said data collected by the federal Centers for Disease Control and Prevention, local health departments and others suggest it was “a lot longer than we first believed” — most likely since “back in December.”
“This wasn’t recognized because we were having a severe flu season,” Smith said in an interview. “Symptoms are very much like the flu. If you got a mild case of COVID, you didn’t really notice. You didn’t even go to the doctor. The doctor maybe didn’t even do it because they presumed it was the flu.”
Just as New York has strong ties to travelers from Europe, who are believed to have brought the coronavirus there from Italy, the Bay Area is a natural hub for those traveling to and from China. Santa Clara County had its first two cases of COVID-19 almost a week before federal approval of emergency testing for the disease Feb. 4. Both were in travelers returning from Wuhan, China, where the virus was rampant.
The CDC provided testing materials to only some health departments, with restrictions that confined testing and thus the tracking of the novel coronavirus to those who were sick or exposed to someone already known to have COVID-19. The federal agency’s focus was on cruise ships, with Princess Cruises’ Diamond Princess carrying the largest known cluster of COVID-19 cases outside of China. The first passenger tested positive for COVID-19 five days after the ship’s Jan. 20 departure from Japan. Eventually, 712 passengers and crew tested positive, and nine of them died.
COVID-19 did not reappear in the Bay Area until Feb. 27, when doctors finally decided to test a hospitalized woman who had been ill for weeks. She became the region’s first case of community-spread coronavirus.
But from there, almost every positive test pointed toward local spread. “When public health [officials] tried to track down the start of the disease … we weren’t able to find, specifically, a contact,” Smith told county supervisors. “That means the virus is in the community already — not, as was suspected by the CDC, as only in China and being spread from contact with China.”
Researchers still unsure how long the virus lurked are now turning to blood banks and other repositories to see if lingering antibodies can show them what was missed. A study funded by the National Institutes of Health is looking for virus antibodies in samples from blood banks in Los Angeles, San Francisco and four other cities across the country.
Azar Ahrabi, 68, died March 9, the second COVID-19 fatality in California, five days after the first. For the first few weeks, the urban county that sits at the heart of Silicon Valley, home to Stanford University and tech giants Apple and Google, led California in coronavirus deaths.
Health investigators said they could find no source of Ahrabi’s infection. Her family members said she stayed mostly at home, taking care of her mother. She seldom drove, and she walked to a local grocery store to shop. But she and her mother lived in a Santa Clara apartment complex in a neighborhood with a high density of international residents.
Relatives said she showed signs of illness in mid-February. For more than a week, they gave only a passing thought that her fever and sudden fatigue might be tied to the horrifying news out of China.
Ahrabi’s son, Amir, said that when his mother checked into a medical clinic Feb. 20 and was diagnosed with a nonspecific pneumonia, she was prescribed antibiotics and sent home. The next day, her doctor admitted her to the intensive care unit.
Amir said he asked that she be tested for COVID-19, and doctors told him the county health department would not approve the test. She met none of the qualifying criteria.
New studies out of Stanford University and the CDC, taken together, suggest that the novel coronavirus spread quickly through the Bay Area.
Stanford’s virology lab, looking retroactively at some 2,800 patient samples collected since January, did not find the first COVID-19 cases until late February — from two patients who were tested Feb. 21 and Feb. 23. Neither of those patients, the researchers note in a letter published by the Journal of the American Medical Assn., would have met existing criteria for COVID-19 testing.
The California Department of Public Health and the CDC did not begin community surveillance for COVID-19 in Santa Clara County until March 5. Samples were collected from 226 coughing, feverish patients who visited four urgent care centers; 1 in 4 turned out to have the flu. The state tested samples from a subset of 79 non-flu patients. Nine of them had COVID-19.
The result suggested that 8% of people walking into the urgent care centers carried the novel coronavirus, an infection rate that mirrored the 5% infection rate at a Los Angeles medical center, the CDC said in a report published Friday.
Pinsky said the virtual invisibility of COVID-19 in February followed by an 8% infection rate two weeks later is not “incompatible…. I think that all kind of fits together.”
Santa Clara County acted on the CDC’s local sampling immediately. Two days after the project ended, it and five other Bay Area counties ordered residents to stay home and schools and nonessential businesses to close. Azar Ahrabi by then was dead.
Amir said he sees his mother as on the cruel side of history, falling ill before Californians were ready to look for the virus already in their presence. For his mother, that realization came too late.
The first confirmed COVID-19 death in California was March 4 in Placer County, claiming the life of a 71-year-old man who had recently taken a Mexican cruise. A ship medical officer told The Times the man had developed symptoms during the Feb. 11-21 voyage, suggesting he brought the virus on board from California.
Two days later, March 6, San Jose authorities found a 70-year-old man dead in his home. The Santa Clara County medical examiner determined the man tested positive for COVID-19, according to records provided to The Times. The discovery of this second death was never publicly announced, and county health officials did not answer questions about the case.
Research by The Times showed he lived less than four miles from Azar Ahrabi, essentially off the same main road with an interstate between them.
The diagnosis of Ahrabi appeared to the family to make little difference in her steady decline. She was put into an induced coma and intubated with a ventilator. Family members were not allowed to see her. The county put them in quarantine and served a legal order to back that up.
Physicians threw a slew of treatments at Ahrabi — including offering a controversial synthetic quinine used to treat malaria but using another experimental treatment, Remdesivir. But her liver failed, and her body rejected dialysis treatment. The ventilator could not deliver enough oxygen through her occluded lungs, and the hospital did not have a machine to infuse oxygen directly into her blood.
“She was essentially tested a week and a half after her first symptoms, and some of the treatments that were proposed and [that] we went with could have been way more effective if we — they — put them in place days ago,” Amir said.
Amir was ordered by Santa Clara County to go into quarantine the day his mother’s test result came back, and he never saw her alive again.
As she died, he stayed in his apartment with his grandmother, caring for the elderly woman without telling her the fate of her daughter. Only after the quarantine order was lifted, when the whole family could again gather, did they tell her Azar Ahrabi had died.
Iranian tradition dictated that the family wash her body and prepare it to eventually return to the earth, Amir said. Instead, the county health department required that she be sealed into a plastic bag for interment.
https://www.latimes.com/california/story/2020-04-11/bay-area-coronavirus-deaths-signs-of-earlier-spread-california
China’s CanSino Bio advances COVID-19 vaccine to phase 2 on prelim safety data
In the global race to develop an effective vaccine to protect people
against the novel coronavirus, China’s CanSino Bio has leapt ahead.
CanSino and its collaborators at the Academy of Military Medical Sciences’ Institute of Biotechnology plan to move their adenovirus type-5 vector-based recombinant COVID-19 vaccine, Ad5-nCoV, into phase 2 clinical trial in China “soon,” the company said in a disclosure (PDF) to the Hong Kong Stock Exchange on Thursday.
The company said the partnership made the decision “[b]ased on the preliminary safety data of the phase 1 clinical trial,” detailed results of which have not been shared.
In fact, virtual enrollment of the phase 2 study where interested
individuals can sign up via a QR code has already started, putting
CanSino ahead of all the others on a long list of COVID-19 vaccine
developers.
It was only in mid-March when CanSino kicked off the first-in-human trial of Ad5-nCoV in healthy volunteers in the city of Wuhan, then the epicenter of the outbreak. Moving a vaccine from phase 1 into phase 2 in just three weeks is super fast, if not unprecedented, even with all the urgency around an ongoing pandemic, making the process look more like a phase 1/2 paradigm.
Per the phase 1 trial design, 108 subjects are supposed to be followed for up to six months for analyses of safety as well as T-cell and antibody responses. The study’s primary endpoint was set to look at adverse reactions seven days post injection, data CanSino likely already have.
According to the phase 2 protocol CanSino’s partner posted Friday on China’s clinical trial registry, the new study will again be conducted in Wuhan and will enroll 500 healthy participants. It’s worth noting that the investigators have abandoned the highest dose used in the phase 1 trial. This time, 250 people will get the middle dose, and the remaining 250 will be split up to receive either the low dose or placebo.
The randomized study has three primary endpoints, which will examine adverse reactions within the first 14 days of vaccination as well as serum levels of anti-SARS-CoV-2 neutralizing antibody and antibody against the coronavirus’s spike protein at day 28. Again, all participants will be followed for up to six months.
Previously, Moderna, in partnership with the National Institutes of Health, was the first to start testing a COVID-19 shot in humans. The Cambridge, Massachusetts-based biotech has an mRNA candidate, mRNA-1273. It contains genetic messages encoding for a stabilized form of the spike protein the coronavirus uses to infect host cells.
Moderna isn’t so far behind. In a recent interview with CNBC, Moderna Chairman Noubar Afeyan said the company’s hopeful it could enter phase 2 “in the spring, perhaps early summer.” In a securities filing, the company said that it might seek emergency use of the vaccine and make it available to some people, including healthcare professionals, possibly in the fall of 2020.
Vaccines are viewed a key step in the world’s transition from the current pandemic to business as usual. According to a road map compiled by experts including former FDA commissioners Scott Gottlieb and Mark McClellan, the current social distancing restrictions can only be lifted when safe and effective tools for mitigating the risk of the disease—including a vaccine—are available.
https://www.fiercepharma.com/vaccines/china-s-cansino-bio-advances-covid-19-vaccine-into-phase-2-preliminary-safety-data
CanSino and its collaborators at the Academy of Military Medical Sciences’ Institute of Biotechnology plan to move their adenovirus type-5 vector-based recombinant COVID-19 vaccine, Ad5-nCoV, into phase 2 clinical trial in China “soon,” the company said in a disclosure (PDF) to the Hong Kong Stock Exchange on Thursday.
The company said the partnership made the decision “[b]ased on the preliminary safety data of the phase 1 clinical trial,” detailed results of which have not been shared.
It was only in mid-March when CanSino kicked off the first-in-human trial of Ad5-nCoV in healthy volunteers in the city of Wuhan, then the epicenter of the outbreak. Moving a vaccine from phase 1 into phase 2 in just three weeks is super fast, if not unprecedented, even with all the urgency around an ongoing pandemic, making the process look more like a phase 1/2 paradigm.
Per the phase 1 trial design, 108 subjects are supposed to be followed for up to six months for analyses of safety as well as T-cell and antibody responses. The study’s primary endpoint was set to look at adverse reactions seven days post injection, data CanSino likely already have.
According to the phase 2 protocol CanSino’s partner posted Friday on China’s clinical trial registry, the new study will again be conducted in Wuhan and will enroll 500 healthy participants. It’s worth noting that the investigators have abandoned the highest dose used in the phase 1 trial. This time, 250 people will get the middle dose, and the remaining 250 will be split up to receive either the low dose or placebo.
The randomized study has three primary endpoints, which will examine adverse reactions within the first 14 days of vaccination as well as serum levels of anti-SARS-CoV-2 neutralizing antibody and antibody against the coronavirus’s spike protein at day 28. Again, all participants will be followed for up to six months.
Previously, Moderna, in partnership with the National Institutes of Health, was the first to start testing a COVID-19 shot in humans. The Cambridge, Massachusetts-based biotech has an mRNA candidate, mRNA-1273. It contains genetic messages encoding for a stabilized form of the spike protein the coronavirus uses to infect host cells.
Moderna isn’t so far behind. In a recent interview with CNBC, Moderna Chairman Noubar Afeyan said the company’s hopeful it could enter phase 2 “in the spring, perhaps early summer.” In a securities filing, the company said that it might seek emergency use of the vaccine and make it available to some people, including healthcare professionals, possibly in the fall of 2020.
Vaccines are viewed a key step in the world’s transition from the current pandemic to business as usual. According to a road map compiled by experts including former FDA commissioners Scott Gottlieb and Mark McClellan, the current social distancing restrictions can only be lifted when safe and effective tools for mitigating the risk of the disease—including a vaccine—are available.
https://www.fiercepharma.com/vaccines/china-s-cansino-bio-advances-covid-19-vaccine-into-phase-2-preliminary-safety-data
Spain sets out back-to-work guidelines as coronavirus death rate slows
Spain’s government on Saturday set out guidelines for people
returning to work under a loosening of lockdown restrictions, while the
country reported its lowest one-day increase in deaths from the
coronavirus since March 23.
Most Spaniards have been confined to their homes since mid-March with
only businesses in sectors deemed strategically important allowed to
operate normally.
However, from Monday, some other industries such as construction and manufacturing will be allowed to restart, enabling thousands to return to work.
Under guidelines issued by the prime minister’s office on Saturday, companies returning to work must provide appropriate protective equipment and ensure employees have space to be at least two metres apart.
Amid concerns it may be too early to begin unwinding the lockdown measures, however, Interior Minister Fernando Grande-Marlaska sought to downplay the change in the rules.
“We are still in the confinement phase… We haven’t begun any relaxation (of the restrictions)” he said at a joint press conference with Health Minister Salvador Illa.
Security forces will distribute 10 million masks at public transport hubs in the coming days, Marlaska said, adding that their use was recommended but not compulsory.
But some politicians criticised the government for failing to provide details of its plans.
“Neither the Madrid region nor any other local transport authority has any information about the distribution of masks announced by the Health Minister,” Madrid’s transport chief Angel Garrido wrote in a tweet.
The slowdown is an encouraging sign for Spain, which reported as many as 950 deaths in one day in early April, and which has suffered the third-highest number of deaths from the virus after Italy and the United States.
The country’s medical workers have been hit particularly hard. Deputy health emergency chief Maria Jose Sierra said some 25,000 healthcare staff had been infected so far, representing about 15% of all confirmed cases.
Medical workers at the Severo Ochoa hospital in the Madrid region fought back tears and applauded at an impromptu wake for a 57-year-old nurse who died after becoming infected with the virus, Reuters Television footage showed.
A banner reading ‘Esteban, always with us’ hung from the wall, while his old scrubs were taped to a window.
The lockdown has caused major disruption to the Catholic country’s Easter celebrations, forcing clergy and worshippers to devise creative ways to participate.
In the eastern town of Villar del Arzobispo near Valencia, priest Raul Garcia held mass with photographs of his parishioners pinned to the pews, and invited them to watch the service online from home.
https://www.reuters.com/article/us-health-coronavirus-spain/spain-sets-out-back-to-work-guidelines-as-coronavirus-death-rate-slows-idUSKCN21T0DJ
However, from Monday, some other industries such as construction and manufacturing will be allowed to restart, enabling thousands to return to work.
Under guidelines issued by the prime minister’s office on Saturday, companies returning to work must provide appropriate protective equipment and ensure employees have space to be at least two metres apart.
Amid concerns it may be too early to begin unwinding the lockdown measures, however, Interior Minister Fernando Grande-Marlaska sought to downplay the change in the rules.
“We are still in the confinement phase… We haven’t begun any relaxation (of the restrictions)” he said at a joint press conference with Health Minister Salvador Illa.
Security forces will distribute 10 million masks at public transport hubs in the coming days, Marlaska said, adding that their use was recommended but not compulsory.
But some politicians criticised the government for failing to provide details of its plans.
“Neither the Madrid region nor any other local transport authority has any information about the distribution of masks announced by the Health Minister,” Madrid’s transport chief Angel Garrido wrote in a tweet.
DEATH TOLL SLOWS
An overnight death toll of 510 brought the total number of fatalities up to 16,353, the Health Ministry said in a statement. Confirmed cases of the infection climbed to 161,852 from 157,022 a day earlier.The slowdown is an encouraging sign for Spain, which reported as many as 950 deaths in one day in early April, and which has suffered the third-highest number of deaths from the virus after Italy and the United States.
The country’s medical workers have been hit particularly hard. Deputy health emergency chief Maria Jose Sierra said some 25,000 healthcare staff had been infected so far, representing about 15% of all confirmed cases.
Medical workers at the Severo Ochoa hospital in the Madrid region fought back tears and applauded at an impromptu wake for a 57-year-old nurse who died after becoming infected with the virus, Reuters Television footage showed.
The lockdown has caused major disruption to the Catholic country’s Easter celebrations, forcing clergy and worshippers to devise creative ways to participate.
In the eastern town of Villar del Arzobispo near Valencia, priest Raul Garcia held mass with photographs of his parishioners pinned to the pews, and invited them to watch the service online from home.
https://www.reuters.com/article/us-health-coronavirus-spain/spain-sets-out-back-to-work-guidelines-as-coronavirus-death-rate-slows-idUSKCN21T0DJ
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